Acute pancreatitis is a common clinical problem which remains evasive of specific therapy..sup.1 Each year more than 15,000 admissions to U.S. hospitals are caused by acute pancreatitis. It is most often caused by alcoholism or biliary tract disease. Less commonly, it is associated with hyperlipemia, hyperparathyroidism, abdominal trauma, vasculitis or uremia. The average length of hospitalization for the disease is 12.4 days, with a significant number of patients staying much longer because of associated complications.
There are no medical therapies or pharmacologic agents currently available which have been shown to decrease the severity, duration, complication rate, or mortality for this common disease. Over the past decade, a somatostatin analog has undergone several clinical, as well as laboratory trials, in an attempt to show beneficial effects of suppressing pancreatic exocrine function pharmacologically during acute pancreatitis. The majority of investigators have shown beneficial effects only with treatment prior to the onset of pancreatitis, and disappointing results when somatostatin was given after the acute inflammatory process had started..sup.2,3,4
With more recent understanding of the complex mechanisms of tissue and cellular injury associated with inflammatory processes, such as sepsis,.sup.5 it is reasonable to assume that many of these inflammatory processes are not specific to sepsis syndromes alone. Several authors have suggested that much of the intrinsic pancreatic damage seen in acute pancreatitis is due to the release of toxic substances from macrophages and other white blood cells which migrate into the damaged gland..sup.6,7,8,9,10,11,12 These substances are known as cytokines and are now well known as mediators of inflammation and tissue injury.
A curious aspect of acute pancreatitis is the systemic response which is seen following inflammation initiated within the pancreas. Acute pulmonary, renal, and hepatic failure, generalized water retention, hypocalcemia, hypoxia, and acid/base disturbances are all possible complications of pancreatitis. The mechanism for complications of pancreatitis. The mechanism for the involvement of these other organ systems is unclear, but probably involves activation of the cytokine cascade, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) in a manner not significantly different from sepsis syndromes..sup.12,13,14,15 Serum levels of these peptides have been shown to correlate to a high degree with the severity of acute pancreatitis in humans, and can also be demonstrated within pancreatic ascites..sup.12,16
The administration of IL-1 to rabbits.sup.17,18,19,20 and primates.sup.21 has been shown to result in hypotension, tachycardia, lung edema, renal failure, and, eventually, death, depending on the dose. These signs and symptoms are similar to those demonstrated by patients with severe acute pancreatitis. When the serum from the IL-1 treated animals is examined, the elevation of other cytokines is evident, mimicking the levels seen in acute pancreatitis in humans..sup.11,12 There is a large body of evidence currently available which supports the role of IL-1 as a major mediator of the systemic response to diseases such as sepsis and pancreatitis and as an activator of the remaining members of the cytokine cascade..sup.5 Fischer et al..sup.21 demonstrated that the administration of a naturally occurring antagonist to IL-1 will significantly blunt the cytokine cascade and improve survival in baboons given a lethal dose of live bacteria. In this study, IL-1 receptor antagonist (IL-1ra) significantly attenuated the decrease in mean arterial pressure and cardiac output and improved survival over control. The systemic IL-1 and IL-6 responses observed as a result of the bacteremia were diminished significantly, correlating with a decrease in the systemic response to the sepsis.
Studies by Aiura et al..sup.20 have shown that IL-1ra is protective in a rabbit model of hypotensive gram-positive septic shock. The administration of IL-1ra in this animal model has been shown to maintain mean arterial pressure compared to control, as well as decreasing lung water and maintaining urine output. This work demonstrated the role of IL-1 and the protective role of IL-1ra in gram-positive shock which was thought to be due to a separate mechanism from gram-negative shock. The common pathway for the systemic manifestations of these two different models of shock has been shown to involve IL-1 as a central mediator. Evidence is mounting for the role of IL-1 as the principal mediator in a patient's clinical response to multiple different stresses regardless of the etiology (including acute pancreatitis).
U.S. Pat. Nos. 4,522,827 and 4,902,708 disclose methods of treating acute pancreatitis. However, none of these patents take into effect the specific pathology of the disease, thereby proposing treatments which are not specific and are directed to the symptoms only, not the underlying mechanism.
U.S. Pat. No. 5,196,402 discloses the use of S-adenosyl methionine for the use of treatment of pancreatitis in the context of a complication in the graft rejection inpancreas transplant, a very uncommon procedure. The patent does not address acute pancreatitis as a disease in the nontransplant patient. The vast majority of cases of pancreatitis are not associated with pancreatic transplants.
Treatments are needed which take into account that the local, as well as systemic, effects seen during acute pancreatitis are due to activation of the cytokine cascade whereby proximal inhibition of this cascade will decrease the severity of the inflammatory process.